Network perturbation-based biomarkers of depression and treatment response
Authors: Florian Müller-Dahlhaus, Til Ole Bergmann
Journal: Cell Reports Medicine (2023)

Using concurrent TMS-EEG, Han et al.1Han S. Li X.X. Wei S. Zhao D. Ding J. Xu Y. Yu C. Chen Z. Zhou D.-S. Yuan T.-F. Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: a randomized double-blind trial and TMS-EEG study.Cell Rep. Med. 2023; 4101060https://doi.org/10.1016/j.xcrm.2023.101060Abstract Full Text Full Text PDF Google Scholar identified temporal and spectral signatures of depression in a prefrontal-orbitofrontal-hippocampal network, which renormalized after rTMS. This highlights the relevance of causal network perturbation for the assessment of disease-related network states and their therapeutic modulation. Using concurrent TMS-EEG, Han et al.1Han S. Li X.X. Wei S. Zhao D. Ding J. Xu Y. Yu C. Chen Z. Zhou D.-S. Yuan T.-F. Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: a randomized double-blind trial and TMS-EEG study.Cell Rep. Med. 2023; 4101060https://doi.org/10.1016/j.xcrm.2023.101060Abstract Full Text Full Text PDF Google Scholar identified temporal and spectral signatures of depression in a prefrontal-orbitofrontal-hippocampal network, which renormalized after rTMS. This highlights the relevance of causal network perturbation for the assessment of disease-related network states and their therapeutic modulation. Repetitive transcranial magnetic stimulation (rTMS) of the left dorsolateral prefrontal cortex (DLPFC) is a safe, effective, and well-tolerated treatment for depression.2Lefaucheur J.-P. Aleman A. Baeken C. Benninger D.H. Brunelin J. Di Lazzaro V. Filipović S.R. Grefkes C. Hasan A. Hummel F.C. et al.Evidence-based guidelines on the therapeutic use of repetitive transcranial magnetic stimulation (rTMS): An update (2014-2018).Clin. Neurophysiol. 2020; 131: 474-528https://doi.org/10.1016/j.clinph.2019.11.002Crossref PubMed Scopus (681) Google Scholar,3Hyde J. Carr H. Kelley N. Seneviratne R. Reed C. Parlatini V. Garner M. Solmi M. Rosson S. Cortese S. Brandt V. Efficacy of neurostimulation across mental disorders: systematic review and meta-analysis of 208 randomized controlled trials.Mol. Psychiatry. 2022; 27: 2709-2719https://doi.org/10.1038/s41380-022-01524-8Crossref PubMed Scopus (21) Google Scholar Yet, it is still unclear which individuals benefit the most, and our understanding of the antidepressant mechanisms of rTMS remains limited, preventing the development of more effective and specific applications. Han et al.1Han S. Li X.X. Wei S. Zhao D. Ding J. Xu Y. Yu C. Chen Z. Zhou D.-S. Yuan T.-F. Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: a randomized double-blind trial and TMS-EEG study.Cell Rep. Med. 2023; 4101060https://doi.org/10.1016/j.xcrm.2023.101060Abstract Full Text Full Text PDF Google Scholar expand our current knowledge on the pathophysiology of depression and the mechanisms underlying rTMS therapy. Using concurrent TMS-electroencephalography (EEG) of the left DLPFC at EEG electrode position F3 to perturb and probe functional brain networks in individuals with major depressive disorder (MDD) in comparison to age-, gender-, and education-matched healthy individuals, they found reduced TMS-evoked brain activity in MDD-affected individuals both locally in left DLPFC and remotely in orbitofrontal cortex (OFC) and hippocampus (HPC). Two weeks (ten sessions) of high-frequency (10 Hz) rTMS targeting the left DLPFC renormalized TMS-evoked brain activity and effective connectivity within the DLPFC-OFC-HPC network and alleviated depressive symptoms, but not anxiety or sleep quality. These findings corroborate the notion that dysfunction of the DLPFC-OFC-HPC network underlies depressive symptoms in MDD and can be specifically targeted and modulated by non-invasive brain stimulation therapies such as rTMS. To improve and personalize the treatment of depression, biomarkers offer great potential for the stratification of affected individuals to select their respective best therapy based on pathophysiological features, thus enhancing the efficacy and specificity of currently available antidepressant treatments.4Arns M. van Dijk H. Luykx J.J. van Wingen G. Olbrich S. Stratified psychiatry: Tomorrow's precision psychiatry?.Eur. Neuropsychopharmacol. 2022; 55: 14-19https://doi.org/10.1016/j.euroneuro.2021.10.863Crossref PubMed Scopus (22) Google Scholar Importantly, not all relevant features of disease-related network dysfunction are directly observable. While alterations of neural excitation may show in spontaneous network activity recorded with neuroimaging techniques, altered neural excitability may require an active stimulus (e.g., a task or neurostimulation) to perturb the system and measure its immediate response. In line with the former, applying machine-learning-based analyses of resting-state EEG data, recent work reported an EEG signature, which predicted treatment outcome with the antidepressant sertraline and might also support treatment selection between medication and rTMS.5Wu W. Zhang Y. Jiang J. Lucas M.V. Fonzo G.A. Rolle C.E. Cooper C. Chin-Fatt C. Krepel N. Cornelssen C.A. et al.An electroencephalographic signature predicts antidepressant response in major depression.Nat. Biotechnol. 2020; 38: 439-447https://doi.org/10.1038/s41587-019-0397-3Crossref PubMed Scopus (115) Google Scholar In contrast, the current study by Han and colleagues1Han S. Li X.X. Wei S. Zhao D. Ding J. Xu Y. Yu C. Chen Z. Zhou D.-S. Yuan T.-F. Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: a randomized double-blind trial and TMS-EEG study.Cell Rep. Med. 2023; 4101060https://doi.org/10.1016/j.xcrm.2023.101060Abstract Full Text Full Text PDF Google Scholar used concurrent TMS-EEG6Hernandez-Pavon J.C. Veniero D. Bergmann T.O. Belardinelli P. Bortoletto M. Casarotto S. Casula E.P. Farzan F. Fecchio M. Julkunen P. et al.TMS combined with EEG: Recommendations and open issues for data collection and analysis.Brain Stimul. 2023; 16: 567-593https://doi.org/10.1016/j.brs.2023.02.009Abstract Full Text Full Text PDF Scopus (2) Google Scholar to implement a so-called "perturb and measure approach,"7Paus T. Inferring causality in brain images: A perturbation approach.Philos. Trans. R. Soc. Lond. B Biol. Sci. 2005; 360: 1109-1114https://doi.org/10.1098/rstb.2005.1652Crossref PubMed Scopus (113) Google Scholar allowing them to study the responsiveness of a depression-related network to stimulation of one of its critical nodes, the left DLPFC. In general, by stimulating cortical (and thus directly accessible) nodes of functional brain networks and simultaneously acquiring high-density EEG, this technique allows recording both local and remote brain responses to TMS with reasonable spatial and excellent temporal resolution. Analysis of the recorded EEG data yields topographically localized temporal and spectral features of the brain's response to TMS perturbation, providing indices of cortical excitability and effective connectivity in large-scale brain networks connected to the stimulation site. To exploit the full potential of TMS-EEG, however, several methodological issues need to be carefully considered.6Hernandez-Pavon J.C. Veniero D. Bergmann T.O. Belardinelli P. Bortoletto M. Casarotto S. Casula E.P. Farzan F. Fecchio M. Julkunen P. et al.TMS combined with EEG: Recommendations and open issues for data collection and analysis.Brain Stimul. 2023; 16: 567-593https://doi.org/10.1016/j.brs.2023.02.009Abstract Full Text Full Text PDF Scopus (2) Google Scholar The EEG response to TMS perturbation is a complex mixture of direct neural responses of the targeted network and both neural and non-neural confounds resulting from peripheral co-stimulation.6Hernandez-Pavon J.C. Veniero D. Bergmann T.O. Belardinelli P. Bortoletto M. Casarotto S. Casula E.P. Farzan F. Fecchio M. Julkunen P. et al.TMS combined with EEG: Recommendations and open issues for data collection and analysis.Brain Stimul. 2023; 16: 567-593https://doi.org/10.1016/j.brs.2023.02.009Abstract Full Text Full Text PDF Scopus (2) Google Scholar Reproducibility, interpretation, and predictive power of TMS-EEG data thus decisively depend on the implementation of rigorous experimental designs. Likewise, both local and remote EEG responses depend on the specific parameter settings, e.g., the exact coil position, orientation, and stimulation intensity, which define the induced electric field in the relevant brain tissue.8Pieramico G. Guidotti R. Nieminen A.E. D'Andrea A. Basti A. Souza V.H. Nieminen J.O. Lioumis P. Ilmoniemi R.J. Romani G.L. et al.TMS-Induced Modulation of EEG Functional Connectivity Is Affected by the E-Field Orientation.Brain Sci. 2023; 13: 418https://doi.org/10.3390/brainsci13030418Crossref Scopus (0) Google Scholar Currently, it is not clear which stimulation parameters are optimal for targeting and engaging a specific brain network. In this context, the current study provided evidence of a role of the DLPFC-OFC-HPC network in the pathophysiology of depression and its alleviation by rTMS. However, the reported TMS-EEG biomarkers should not be taken for granted, since a stimulation with parameters targeting slightly different cortical sites in the left DLPFC, thus activating different remote network nodes, may yield very different signatures of depression and treatment response (see Figure 1). A limitation of the TMS-EEG approach is its comparably low spatial resolution and ambiguousness of source localization, in particular for deep brain structures. For increased anatomical precision in the assessment of depression-related brain networks, TMS can be combined with other neuroimaging modalities, such as functional magnetic resonance imaging (fMRI), which provides inferior temporal but exquisite spatial resolution with whole-brain coverage. Concurrent TMS-fMRI can be applied for causal network perturbation and assessment and provides an ideal tool for gaining spatially highly resolved proof of target engagement.9Bergmann T.O. Varatheeswaran R. Hanlon C.A. Madsen K.H. Thielscher A. Siebner H.R. Concurrent TMS-fMRI for causal network perturbation and proof of target engagement.Neuroimage. 2021; 237118093https://doi.org/10.1016/j.neuroimage.2021.118093Crossref Scopus (29) Google Scholar To follow up on the findings of the current study, it would be interesting to prove target engagement of the OFC and HPC following left DLPFC TMS. Likewise, TMS-fMRI could be used to validate rTMS-induced activity changes in this network by studying TMS-evoked blood-oxygen-level-dependent (BOLD) responses in engaged deep brain structures before and after rTMS treatment. Importantly, TMS-fMRI studies have repeatedly demonstrated a strong state dependency of TMS-evoked brain responses, with identical physical stimuli resulting in very different remote network activations depending on, for example, the task or the attentional involvement at the time of stimulation9Bergmann T.O. Varatheeswaran R. Hanlon C.A. Madsen K.H. Thielscher A. Siebner H.R. Concurrent TMS-fMRI for causal network perturbation and proof of target engagement.Neuroimage. 2021; 237118093https://doi.org/10.1016/j.neuroimage.2021.118093Crossref Scopus (29) Google Scholar (see Figure 1). Thus, state-dependent network activation is particularly relevant for the perturbation-based assessment of disease-related networks when planning and evaluating therapeutic rTMS but also during treatment for routing the TMS-induced brain activity to the "right" networks, i.e., those generating specific disease symptoms. In summary, the current study by Han and colleagues1Han S. Li X.X. Wei S. Zhao D. Ding J. Xu Y. Yu C. Chen Z. Zhou D.-S. Yuan T.-F. Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: a randomized double-blind trial and TMS-EEG study.Cell Rep. Med. 2023; 4101060https://doi.org/10.1016/j.xcrm.2023.101060Abstract Full Text Full Text PDF Google Scholar highlights the potential of perturbation-based biomarkers and provides important new evidence for the dysfunction of a prefrontal-orbitofrontal-hippocampal network in individuals with MDD and its renormalization by rTMS therapy. Future work implementing perturbation-based approaches to study depression-related functional brain networks and their dynamics should focus on the identification of optimal parameter settings for effectively engaging these networks and the investigation of state dependency of network activation and modulation by, for example, cognitive and emotional tasks,10Zrenner C. Belardinelli P. Müller-Dahlhaus F. Ziemann U. Closed-Loop Neuroscience and Non-Invasive Brain Stimulation: A Tale of Two Loops.Front. Cell. Neurosci. 2016; 10: 92https://doi.org/10.3389/fncel.2016.00092Crossref PubMed Scopus (122) Google Scholar with high spatial and temporal resolution. Results from these studies will provide the necessary basis for developing more effective personalized network-based neuromodulation therapies in depression. The authors declare no competing interests. Orbitofrontal cortex-hippocampus potentiation mediates relief for depression: A randomized double-blind trial and TMS-EEG studyHan et al.Cell Reports MedicineMay 31, 2023In BriefHan et al. demonstrate that patients with MDD have reduced activity in the DLPFC, the OFC, the HPC, and DLPFC-OFC connectivity compared with healthy controls. They show that DLPFC-targeted rTMS treatment ameliorates depressive symptoms via the OFC-HPC pathway. Full-Text PDF Open Access